A new general approach for the synthesis of 2-substituted-3H-indol-3-one N-oxide derivatives

Article abstract of DOI:10.1055/s-2001-13368

2-aryl (phenyl, 1,3-benzodioxolyl) and 2-alkyl (ethyl, sec-butyl)-3H-indol-3-one N-oxides were synthesized by a new general method involving a reductive intramolecular cyclization reaction of ortho-diketo nitrobenzene derivatives.

Full text of DOI:10.1055/s-2001-13368

700
LETTER
A New General Approach for the Synthesis of 2-Substituted-3H-indol-3-one
N-Oxide Derivatives
Vania Bernardes Génisson,* Anne-Valérie Bouniol, Françoise Nepveu*
Laboratoire Pharmacophores Redox, Phytochimie et Radiobiologie,UPRES-EA-3030 Université Paul Sabatier, Faculté des Sciences Phar-
maceutiques 35, Chemin des Maraîchers, 31062 Toulouse Cedex 4, France
Fax +33 5 62 25 68 88; E-mail: nepveu@cict.fr, genisson@cict.fr
Received 5 February 2001
Abstract: 2-aryl (phenyl, 1,3-benzodioxolyl) and 2-alkyl (ethyl,
sec-butyl)-3H-indol-3-one N-oxides were synthesized by a new
general method involving a reductive intramolecular cyclization re-
action of ortho-diketo nitrobenzene derivatives.
Key words: isatogens, nitrone, -diketone, intramolecular cycliza-
tion, oxidation
Introduction
2-Substituted-3H-indol-3-one N-oxides, more frequently
named isatogens, are brightly colored solids that do not
occur naturally. Some of them show a variety of biologi-
cal properties such as significant activity against a range
of bacteria,1 mycobacteria2 and fungi3 and are also able to
antagonize the relaxant response to adenosine-5-tri-
phosphate in mammals.4 In addition, they are also able to
trap oxygen and carbon-centered radicals as reported in
different works.5
To date, this type of molecule has been synthesized via
two main methods involving either the oxidation of a 1-
hydroxy-2-substituted indole6 or the intramolecular cy-
clization of an ortho-substituted nitrobenzene precursor7
(Scheme 1). However, the first strategy, applicable to both
alkyl and aryl substituted isatogens, requires a multi-step
preparation of the indole intermediate and the second syn-
thetic approach is limited to 2-aryl 3H-indol-3-one N-ox-
ides. Besides, in most cases, the cyclization reactions
afford the desired nitrone in poor yields or require several
days to reach completion. Thus, synthetic routes towards
isatogens having a wide scope and efficiency are still rare.
We thus report here a simple and general approach to the
synthesis of 2-substituted-3H-indol-3-one N-oxides.
Scheme 1
A retrosynthetic analysis of isatogens led us to propose
the preparation of the cyclic nitrone by a cyclization reac-
tion between a hydroxylamine and a carbonyl group.
Therefore, -diketone 4 appears as a pivotal intermediate
to this approach (Scheme 2).
In order to test the feasibility of this strategy, we firstly
tried to obtain 2-nitro benzil intermediates by condensa-
tion of two aromatic aldehydes 1 and 2 (Scheme 2). For
this purpose, we have synthesized the 1,3-dithiane of pip-
eronal aldehyde. However, under basic conditions (BuLi)
this acyl anion equivalent failed to react with 6-nitropip-
eronal to give the protected form of the desired diketone
Scheme 2
Synlett 2001, No. 5, 700–702 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Substituted-3H-indol-3-one N-Oxide Derivatives
701
4b. Attempts to employ piperonal as electrophilic partner
and 6-nitropiperonal as acyl anion equivalent were also
unsuccessful. We also tried to obtain dione 4 by direct ox-
idation of the corresponding alkene 3 (Scheme 2) which
was in turn prepared in excellent yield by an olefination
reaction8 between ortho-nitrobenzaldehyde derivatives 1
and Wittig phosphonium bromides 7 (Scheme 3). Recent-
ly, Filimonov et al.9 have described a method to transform
carbon-carbon multiple bonds into 1,2-diketones by ac-
tion of HBr/DMSO or I2/DMSO. All our attempts to ob-
tain -diketone from stilbene 3 under these conditions
failed. In contrast, oxidation of a mixture of Z/E-stilbene
3a with potassium permanganate in acetic anhydride,10 af-
forded 4a in 60% yield and ketoacetate 5a in 11% yield.
These compounds were easily separated by column chro-
matography on silica gel (eluent: cyclohexane /ethyl ace-
tate 80:20). The position of the acetate group in 5a could
be unequivocally determined by EI/MS since the bond
between the two central benzylic carbon atoms is easily
cleaved under electron impact conditions. Indeed, the EI/
MS spectrum of 5a showed two peaks at m/z 105 and 135
relative to fragment ions C7H5O and C8H7O2, respective-
ly. Finally, reduction of 4a with Zn(0)/NH4Cl for 20 min
and then heating of the hydroxylamine intermediate in
THF for 3 hours, cleanly afforded 6a11 (91%) whose spec-
tral data are comparable with the literature. Even though a
competitive process resulting from attack of the oxygen
atom at another carbonyl group might be expected,12 it did
not interfere in this case. The hydroxylamine intermediate
was not isolated since cyclization to isatogen takes place
spontaneously under workup conditions.
Scheme 3
A similar result was also obtained with a substituted aryl
derivative. Piperonal intermediate 4b gave isatogen 6b13
in 64% yield. The structure of 6b was confirmed by an un-
ambiguous synthesis via the pyridinium ethanol interme-
diate (Scheme 1) from which 6b could only be obtained in
a poor yield (~10%).
Conclusion
The strategy developed in this work, based on the reduc-
tive intramolecular cyclization of ortho-nitrobenzene pre-
cursors, provides a simple and versatile route to isatogens
bearing both aryl and alkyl substituents in the 2-position.
In the first part of this study, the carbon atom attached to
the 2-position of the isatogen molecule is sp2 hybridized.
In order to extend this route to the preparation of 2-substi-
tuted isatogen molecules with an sp3 carbon atom attached
to the 2-position, we investigated the preparation of alkyl
isatogens where R is ethyl or sec-butyl. The correspond-
ing diketone intermediates 4c and 4d were prepared as re-
ported above in 50% and 66% yield, respectively. In fact,
oxidation of 3c and 3d by the action of KMnO4 is accom-
panied by the formation of ketoacetate 5. It is interesting
to note that the competitive acetylation reaction is regiose-
lective in all cases and that the ketoacetate derivative 5
can be easily recycled to give the corresponding dike-
tone.14 For instance, using methanolic potassium carbon-
ate, the ketoacetate 5c was saponified to the
corresponding -hydroxy ketone which was in turn oxi-
dized by cupric acetate to dione 4c with an overall yield of
68%. Under the same cyclization conditions as above,
diketones 4c and 4d led to the formation of the desired
isatogen derivatives 6c15 and 6d,16 respectively.
Acknowledgement
This research was supported, in part, by grants from the ARC Foun-
dation (n° 5358).
References and Notes
(1) Hooper, M.; Patterson, D. A.; Wibberley, D. G. J. Pharm.
Pharmacol. 1965, 17, 734.
(2) Sahasrabudhe, A. B.; Kamath, H. V.; Bapat, B. V.; Kulkarni,
S. N. Indian J. Chem. 1980, 19B, 230.
(3) Helmut, H.; Rolf-Dieter, K.; Ernst-Heinrich, P.; D E Patent
3047388, Eur Pat 54147 (1982); Chem. Abstract 1982, 97,
216185q.
(4) Speeding, M.; Sweetman, A. J.; Weetman, D. F. Brit. J.
Pharmac. 1975, 53, 575. Beechey, R. B.; Cattell, K. J.; Green,
A. P.; Hooper, M.; Lindop, C. R.; Sweetman, A. J. Biochem.
Soc. Trans. 1 1973, 410. Hooper, M.; Spedding, M.;
Sweetman, A. J.; Weetman, D. F. Proc. Brit. Pharmacol. Soc.
1974, 458 P.
Synlett 2001, No. 5, 700–702 ISSN 0936-5214 © Thieme Stuttgart · New York

702
V. B. Génisson et al.
LETTER
(5) Colonna, M.; Greci, L.; Marchetti, L. Gazz. Chim. Ital. 1979,
109, 29. Nepveu, F.; Souchard, J.-P.; Rolland, Y.; Dorey, G.;
Speeding, M. Biochem. Biophys. Res. Commun. 1998, 242,
272. Rosen, G. M.; Tsai, P.; Barth, E. D.; Dorey, G.; Casara,
P.; Speeding, M.; Halpern, H. J. J. Org. Chem. 2000, 65, 4460.
(6) Bristow, T. H. C.; Foster, H. E.; Hooper, M. J. Chem. Soc.,
Chem. Commun. 1974, 677. Bond, C. C.; Hooper, M.
Synthesis 1974, 443.
(7) Ruggli, P.; Cuenin, H. Helv. Chim. Acta 1944, 27, 649.
Kröhnke, F.; Meyer-Delius, M. Chem. Ber. 1951, 84, 932.
Kröhnke, F; Vogt, I. Chem. Ber. 1952, 85, 376. Patterson, D.
A.; Wibberley, D. G. J. Chem. Soc. 1965, 1706. Bond, C. C.;
Hooper, M. J. Chem. Soc. (C) 1969, 2453. Bhamare, N. K;
Kamath, H. V.; Kulkarni, S. N. Indian J. Chem. 1986, 25B,
613. Kulkarni, S. N.; Kamath, H; V.; Bhamare, N. K. Indian
J. Chem. 1988, 27B, 667.
(12) Hiremath, S. P.; Hooper, M. Adv. Heterocycl. Chem. 1978, 22,
123.
(13) Isatogen 6b in solution (CH2Cl2) presents a violet color. Rf:
0.38 (cyclohexane/ethyl acetate 80:20). M.p. = 202-204 °C
(decomposition). IR (KBr) cm-1: 2915.1; 1702.8 ( C = O);
1471.7; 1301.9; 1259.4 ( C-O-C); 1188.7; 1103.8; 1033.0;
806.6. 1H NMR (CDCl3, 200 MHz) ppm 5.99 (s, 2H); 6.10
(s, 2H); 6.88 (d, J = 8.5 Hz, 1H); 6.96 (s, 1H); 7.10 (s, 1H);
8.20 (d, J = 1.4 Hz, 1H); 8.28 (dd, J = 8.5 Hz and 1.8 Hz, 1H).
13C NMR (CDCl3, 100 MHz) ppm 97.5 (CH), 101.7
(CH2), 102.5 (CH), 103.3 (CH2), 107.5 (CH), 108.8 (CH),
116.6 (C), 120.4 (C), 123.5 (CH), 131.3 (C), 145.0 (C), 147.8
(C), 149.5 (C), 149.6 (C), 153.1 (C), 186.2 (C). FAB/MS m/z:
312 (M++1); 295 (M+ - 16); 149.
(14) Cope, A. C.; Fordice, M. W. J. Am. Chem. Soc. 1967, 89,
6187. Rozwadowska, M. D.; Chrzanowska, M. Tetrahedron
1985, 41, 2885.
(8) Tolstikov, G. A.; Miftakhov, M. S.; Adler, M. E.;
Komissarova, N. G.; Kuznetsov, O. M. Vostrikov, N. S.
Synthesis 1989, 940.
(9) Yusubov, M. S.; Filimonov, V. D.; Vasilyeva, V. P.; Chi, K-
W. Synthesis 1995, 1234.
(15) Compound 6c: dark red solid. Rf: 0.41 (cyclohexane/ethyl
acetate 80:20). M.p. = 136 °C. IR (KBr) cm-1: 3084.9; 2896.5;
1698.1 ( C = O); 1542.5 ( C = N); 1471.7; 1462.3; 1358.5;
1306.6; 1287.7 ( C-O-C); 1217.0; 1122.6; 1075.5; 1037.7;
957.5. 1H NMR (CDCl3, 200 MHz) δ (ppm,): 1.18 (t, J = 7.6
Hz, 3H); 2.61 (q, J = 7.6 Hz, 2H); 6.11 (s, 2H); 6.95 (s, 1H);
7.08 (s, 1H). NMR 13C NMR (CDCl3, 100 MHz) ppm 9.9
(CH3), 15.2 (CH2), 97.5 (CH), 102.5 (CH), 103.2 (CH2), 117.0
(C), 139.1 (C), 144.4 (C), 149.6 (C), 152.5 (C), 185.9 (C). EI/
MS m/z : 219 (M+); 202 (M+ - 17); 174; 120; 62.
(16) Compound 6d : yellow solid. Rf : 0.59 (cyclohexane / ethyl
acetate 80:20). M.p. = 101-102 °C. IR (KBr) cm-1: 3102.1;
3083.2; 2960.3; 1700.4 ( C = O); 1601.1 ( C = C); 1530.3 (
C = N); 1459.4; 1431.0; 1374.3; 1161.6; 1076.6; 906.4; 764.7;
533.1. 1H NMR (CDCl3, 200 MHz) : ppm 0.95 (d, J = 6.6
Hz, 6H); 2.17 (m, 1H); 2.55 (d, 2H); 7,54 (m, 4H). 13C NMR
(CDCl3, 100 MHz) ppm 22.8 (2 CH3), 26.8 (CH), 30.2
(CH2), 113.9 (CH), 121.4 (CH), 123.1 (C), 131.0 (CH), 134.4
(CH), 139.0 (C), 147.4 (C), 187.1 (C). EI/MS m/z : 203 (M+),
186 (M+ - 17), 161, 144, 116, 89, 76, 50, 43.
(10) Sharpless, K. B.; Lauer, R. F.; Repic, O.; Teranishi, A. Y.;
Williams, D. R. J. Am. Chem. Soc. 1971, 93, 3303.
(11) General experimental procedure for isatogen preparation.
Synthesis of 2-phenyl-3H-indol-3-one N-oxides: To a
solution of 4a (0.150 g, 0.59 mmol) in THF (10 mL) was
added a 10% aq solution of NH4Cl (11 mL) and Zn (0.150 g).
After 20 min of stirring at r.t., the mixture was filtered and the
two liquid phases separated. The organic phase was dried
(Na2SO4) and concentrated in vacuum. The residue was
dissolved in THF (10 mL) and heated under reflux for 4
h. Evaporation of the solvent and purification of the crude
product by column chromatography (SiO2, cyclohexane/ethyl
acetate 80:20) gave 0.120 g (91%) of 6a as a red solid. Rf: 0.58
(cyclohexane/ethyl acetate 80:20). M.p. = 180 °C, m.p.
lit. = 186 °C. IR (KBr) cm-1: 3064.3; 1719.3 ( C = O); 1700.4
( C = O); 1596.4; 1520.8 ( C = N); 1470.3; 1382.1; 1311.3;
1179.2 ( N-O); 1070.8; 872.6; 754.7. 1H NMR (CDCl3, 200
MHz) ppm 8.67-8.62 (m, 2H); 7.74 - 7.45 (m, 7H). 13C
NMR (CDCl3, 100 MHz) ppm 114.8 (CH), 121.9 (CH),
122.8 (C), 125.9 (C), 127.8 (2 CH), 128.5 (2 CH), 130.6
(CH), 131.1 (CH), 133.0 (C), 134.7 (CH), 147.8 (C), 186.7
(C). EI/MS m/z : 223 (M+); 206 (M+ - 17); 105.
Article Identifier:
1437-2096,E;2001,0,05,0700,0702,ftx,en;G02701ST.pdf
Synlett 2001, No. 5, 700–702 ISSN 0936-5214 © Thieme Stuttgart · New York